Evidence for linkage of the apolipoprotein A-II locus to plasma apolipoprotein A-II and free fatty acid levels in mice and humans.

Abstract

Although it has been hypothesized that the synteny between mouse and human genes provides an approach to the localization of genes that determine quantitative traits in humans, this has yet to be demonstrated. We tested this approach with two quantitative traits, plasma apolipoprotein A-Il (apoAll) and free fatty acid (FFA) levels. ApoAII is the second most abundant protein of high density lipoprotein particles, but its function remains largely unknown. We now show that, in a backcross between strains Mus spretus and C57BL/6J, apoAII levels correlate with plasma FFA concentrations on both chow (P < 0.0001) and high-fat (P < 0.0003) diets and that apoAll levels are linked to the apoAII gene (P < 0.0002). To test whether variations of the apoAll gene influence plasma lipid metabolism in humans, we studied 306 individuals in 25 families enriched for coronary artery disease. The segregation of the apoAII gene was followed by using an informative simple sequence repeat in the second intron of the gene and two nearby genetic markers. Robust sib-pair linkage analysis was performed on members of these families using the SAGE linkage programs. The results suggest linkage between the human apoAll gene and a gene controlling plasma apoAII levels (P = 0.03). Plasma apoAII levels were also significantly correlated with plasma FFA levels (P = 0.007). Moreover, the apoAII gene exhibited linkage with a gene controlling FFA levels (P = 0.003). Evidence for nonrandom segregation was seen with markers as far as 6-12 centimorgans from the apoAll structural locus. These data provide evidence, in two species, that the apoAII gene is linked to a gene that controls plasma apoAll levels and that apoAII influences, by an unknown mechanism, plasma FFA levels. The results iliustrate the utility of animal studies for analysis of complex traits.

Evaluation of apolipoprotein A-II as a positional candidate gene for familial Type II diabetes, altered lipid concentrations, and insulin resistance

“…We were only able to show modest evidence for an association of microsatellite alleles 7 and 8 with NEFA concentrations and microsatellite allele 4 and haplotype 2 with triglyceride concentrations and we found no evidence for an association of any variant with HDL cholesterol. These findings seem to contrast the earlier linkage studies of NEFA [6]. The association findings are consistent with our inability to show linkage of these traits to this region using variance component quantitative trait linkage analysis.…”

“…Linkage data in mice and humans [6], in experimental mouse models [43], transgenic mouse models [21,41] and knockout [43] mouse models all support a role for APOA2 in HDL and NEFA metabolism and in insulin sensitivity. Such a pleiotropic effect is consistent with the hypothesis that increased NEFA alter insulin sensitivity, increase hepatic glucose production, and can alter insulin secretion [44,45].…”

“…Given the prior evidence for a role of APOA2 in insulin sensitivity, HDL concentrations, and NEFA concentrations [6,21,41,42,43], we examined the effect of APOA2 variation and haplotypes on ten related traits: NEFA, HDL cholesterol, triglycerides, fasting insulin, fasting glucose, 60 and 120 min glucose during an OGTT and a measure of insulin secretion at 60 min that is normalized for the insulin sensitivity (OCI60; see Methods). Surprisingly, we found little evidence for an effect of either individual variants or haplotypes on triglycerides, HDL cholesterol, NEFA, or fasting insulin.…”

“…Although multiple positional candidate genes exist within the confidence interval for linkage, considerable data support the APOA2 gene as a functional candidate in addition to its location within a well replicated region of linkage. APOA2 was linked to non-esterified fatty acid concentrations (NEFA) in mice and humans [6]. Increased NEFA concentrations have been shown to decrease insulin action in muscle [7], increase hepatic glucose output [8], and possibly alter insulin secretion [9,10,11].…”

Identification of Apolipoprotein A-II in Cerebrospinal Fluid of Pediatric Brain Tumor Patients by Protein Expression Profiling

“…Despite the high abundance of APO A-II, little is known about its biological functions. APO A-II is thought to influence the metabolism of HDL and glucose (31)(32)(33). Genetic variations in APO A-II appear to be involved in senile amyloidogenesis in mice and humans (30,34,35 ), and APO A-II has recently been linked to malignancies.…”